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Inhalable curcumin is a potential treatment for herpes simplex virus type 1-associated Alzheimer’s disease

26 December 2015

Herpes simplex virus type 1 (HSV-1) DNA is frequently detected in the aged brains of both normal individuals and patients with Alzheimer’s disease (AD) [1]. In recent studies, the reactivation of HSV-1 in the brain is a potent risk factor for the development of AD [1]. Reactivated HSV-1 can cause an increased formation and accumulation of amyloid-β (Aβ) and abnormally phosphorylated tau. Moreover, HSV-1-mediated disruption of autophagy in neurons may also contribute to the accumulation of these abnormal proteins [2]. HSV-1 reactivation, as a matter of course, induces various inflammatory responses in the brain tissue that likely impact the pathogenesis of AD.

Accumulating evidence suggests that HSV-1 insidiously invades the human brain through the olfactory pathway and persists in some limbic structures including the hippocampus and frontotemporal cortex [3]. This phenomenon is due to some unique properties of the olfactory system. First, nerve terminals of olfactory receptor neurons are directly exposed to the external environment in the nasal cavity. Second, these neurons are able to uptake exogenous substances and transport them to the limbic system encompassing the hippocampus. Third, the olfactory system is directly connected to the frontal cortex without thalamic relay. It is important to note, there are striking similarities between the patterns of HSV-1 distribution and Aβ deposits in the brains of patients with AD [3].

Curcumin is a natural polyphenol that is extracted from the curry spice turmeric. The preventative and therapeutic roles of curcumin in AD, particularly its neuropharmacological action, have been partially attributed to the anti–HSV-1 activities of polyphenols [4]. Curcumin likely blocks the expression of HSV-1 immediate-early genes by inhibiting the recruitment of RNA polymerase II to the promoters of these essential viral genes [5]. The clinical use of curcumin, however, is restricted due to its poor aqueous solubility and relatively low penetration efficiency across the blood–brain barrier.

McClure et al. recently reported in a JAD article that an aerosolized curcumin derivative, FMeC1, efficiently targets the hippocampus and frontotemporal cortex following intranasal exposure in mice [6]. This compound appears to be transported from the nasal mucosa to these brain areas via the olfactory pathway. Therefore, inhalable curcumin will safely target HSV-1–infected brain tissues and efficiently control virus-induced, AD-related neuropathological alterations.

Isamu Mori, MD
Faculty of Health and Nutrition, Shubun University, Aichi, Japan
E-mail: mori@shubun-ac.jp

References
[1] Itzhaki RF (2014) Herpes simplex virus type 1 and Alzheimer’s disease: increasing evidence for a major role of the virus. Front Aging Neurosci 6, 202.
[2] Mori I (2010) Herpes simplex virus type 1 persists in the aged brain through hypothetical expression of accessory genes. J Neurovirol 16, 203-207.
[3] Mori I (2015) Transolfacotry neuroinvasion by viruses threatens the human brain. Acta Virol 59, 338-349.
[4] Mori I (2015) Anti-herpesviral activity of curcumin may attenuate the development of Alzheimer’s disease. Med Hypotheses 84, 603.
[5] Kutluay SB, Doroghazi J, Roemer ME, Triezenberg SJ (2008) Curcumin inhibits herpes simplex virus immediate-early gene expression by a mechanism independent of p300/CBP histone acetyltransferase activity. Virology 373, 239-247.
[6] McClure R, Yanagisawa D, Stec D, Abdollahian D, Koktysh, D, Xhillari D, Jaeger R, Stanwood G, Chekmenev E, Tooyama I, Gore JC, Pham W (2015) Inhalable curcumin: offering the potential for translation to imaging and treatment of Alzheimer’s disease. J Alzheimers Dis 44, 283-295.